The primary goal of this Program Project is to investigate interactions between the aging brain and female reproductive senescence. Animal studies have demonstrated clearly that changes in circulating estrogen levels affect cellular and molecular attributes of certain neural circuits and related cognitive functions. However, the link between such observations and the human data on peri-and post-menopausal memory impairment, beneficial neurobehavioral effects of estrogen replacement therapy (ERT) or combined hormone replacement therapy (HRT) and protection against Alzheimer's disease are far from clear. Recent studies from the Women's Health Initiative on potential negative effects of a commonly used combined hormone replacement (HR) regimen have brought these issues to the forefront, and reinforced the need for additional scientific data on which to base therapies that are more physiological and beneficial to women. The Program Project mechanism is ideally suited for a full spectrum analysis of the key issues; from signaling mechanisms of estrogen in the brain to an in-depth structural and functional assessment of the effects of estrogen on the circuits regulating reproductive function (hypothalamus), to the effects of estrogen and aging on cognition and related cortical circuits. Projects 1, 2, and 3 will converge on the rodent model for detailed mechanistic and ultrastructural analyses of estrogen-induced plasticity, interactions with progesterone, and alterations in estrogen-induced plasticity due to aging. Core A and Projects 2, 3, 5, and 6 will converge on the nonhuman primate model (NHP) to study similar systems in NHPs treated with one of several clinically relevant HR regimens involving different schedules of estrogen and progesterone replacement. The aged NHPs will have extensive neuropsychological assessment aimed at determining age, estrogen, and progesterone effects on medial temporal lobe and prefrontal functions. We will investigate the neurobiological effects of multiple HR regimens in young and aged NHPs to reveal key synaptic and cellular reflections of estrogen-induced plasticity as well as effects on neurogenesis, and potential modifications induced by progesterone. In the aged animals, we will illuminate the underlying neurobiological events responsible for cognitive enhancement. Such analyses will reveal the HR regimen that most successfully promotes neurobiological and cognitive health in aged monkeys, laying the groundwork for more informed approaches to HRT in humans to promote successful brain aging.